A Study of AK112 in Patients With Advanced Hepatocellular Carcinoma (HCC)

A Phase Ib/II Study of AK112 in Combination Therapy for Patients With Advanced Hepatocellular Carcinoma (HCC)

There're 2 parts in this interventional study:

1. The goal of phase Ib trial is to evaluate the safety and tolerability of AK112 in combination therapies for the purpose of observing the incidence of dose limit toxicity (DLT) as well as the confirmation of maximum tolerable dose (MTD) in the treatment of advanced hepatocellular carcinoma (HCC), so as to determine the recommended phase 2 dose (RP2D) in the second part of the trial.
2. The goal of phase II trial is to evaluate the safety and efficacy of AK112 in combination therapy or monotherapy in the treatment of HCC compared to the combination of Sintilimab and Bevacizumab biosimilar.

Inclusion Criteria:

1. Be able and willing to provide written informed consent.

2. Have a life expectancy of at least 3 months.

3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. HCC confirmed by histology/cytology or confirmed by the American Society for the Study of Hepatology (AASLD) clinical diagnostic criteria for hepatocellular carcinoma in patients with cirrhosis.

5. Phase Ib:

   1. Barcelona Clinical Liver Cancer (BCLC) stage B or C.
   2. Has failed standard treatment and has received no more than two lines of anti-tumor treatment in the past;

   Phase II:

   1. The BCLC staging is stage C, which is not suitable for curative and local treatment, or for stage B that cannot be cured after curative and/or local treatment.
   2. Subjects who have not received any systematic anti-tumor treatment for HCC in the past.

6. According to RECIST v1.1, there is at least one untreatable measurable lesion, or a measurable lesion with clear imaging progression after local treatment, suitable for repeated and accurate measurement.

7. Liver function grading Child Pugh Grade A.

8. Has adequate organ function.

9. All subjects of reproductive potential must agree to use an effective method of contraception, as determined by the Investigator, during and for 120 days after the last dose of study treatment.

10. Able to to comply with all requirements of study participation (including all study procedures).

Exclusion Criteria:

1. Components confirmed by histology/cytology, such as fibrous layer hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, and cholangiocarcinoma.
2. Except for HCC, the subjects had other malignant tumors within the 5 years prior to enrollment. Subjects with other malignant tumors that have been cured through local treatment are not excluded, such as basal or cutaneous squamous cell carcinoma, superficial bladder cancer, cervical or breast cancer in situ. If diagnosed with liver cancer or other malignant tumors more than 5 years before administration, pathological or cytological diagnosis of recurrent and metastatic lesions is required.
3. Tumor volume>50% liver volume; Portal vein cancer thrombus (Vp4), inferior vena cava cancer thrombus.
4. Tumors invade important organs and blood vessels around them, and researchers have determined that entering the study will cause a higher risk of bleeding.
5. There is central nervous system (CNS) metastasis, spinal cord compression, or meningeal metastasis.
6. There are pleural effusion, pericardial effusion, or ascites with clinical symptoms or requiring repeated drainage.
7. Previously received immunotherapy, including immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapy, and any other treatments targeting the immune mechanisms of tumors.
8. Received local treatment for the liver within 4 weeks prior to the first administration; Received palliative radiotherapy for non liver patients within 2 weeks prior to initial administration.
9. There is a history of non infectious pneumonia that requires systemic glucocorticoid treatment, or current lung diseases including but not limited to interstitial lung disease, pneumoconiosis, silicosis, drug-related pneumonia, and severely impaired lung function.
10. History of severe bleeding tendency or coagulation dysfunction.
11. Previous history of myocarditis, cardiomyopathy, and malignant arrhythmia.
12. Any arterial or venous thromboembolism events, transient ischemic attacks, cerebrovascular accidents, hypertensive crises, or hypertensive encephalopathy occurred within 6 months prior to the first administration of medication.
13. Pregnant or lactating female subject.
14. Any prior or concurrent disease, treatment, or laboratory test abnormality that may confuse study results, affect subjects' full participation in the study, or may not be in their best interest to participate.